The long range goal of the project is to better understand the pathobiochemical causes of cataracts. Cataracts are the leading cause of blindness worldwide, and in the U.S. cataracts are responsible for more surgical procedures than any other cause. Better understanding of the biochemical causes and effects of cataracts eventually may lead to their early diagnosis and nonsurgical treatment. The proposed research focuses on the balance between biological stress and repair processes in lenses. Increased phospholipid (PL) synthesis occurs during formation of diabetic and galactosemic cataracts and some hereditary cataracts. This suggests the hypothesis that one mechanism by which normal lenses resist stress and prevent cumulative deterioration of cells is by regulating PL synthesis in a controlled response to provide the PL necessary for growth and for repair of damaged membranes. Lenses will be subjected to cataractogenic stress in vivo (e.g., galactosemic rats) and in culture (e.g., oxidatively stressed cultured human lens epithelial cells). Sensitive radiotracer techniques will be used to measure PL synthesis in lenses, concentric layers from lenses, and lens cells. The hypothesis predicts that PL synthesis will increase as lenses are stressed and swell, and that it will return to a baseline rate when swelling is reversed. Also, if the increased PL synthesis is for membrane growth or repair, the changes in rates of synthesis of various classes of membrane PLs should be coordinated. Finally, the hypothesis suggests that there is a threshold of stress that exceeds the ability of lenses for membrane repair. Since there is evidence that normal PL synthesis in lenses can be disrupted when stress reaches a threshold level, this could lead to a self-reinforcing cycle of membrane damage, decreased repair, and more membrane damage. If the results of the proposed experiments support these predictions and the hypothesis, then the it may be possible to find means to protect lenses and maintain stress levels below the threshold and prevent cumulative lens damage and cataract. If the hypothesis is false, then the increased PL synthesis in cataracts may only be a symptom of the degenerative process, there may be no threshold stress level, and even very low levels of damage may be cumulative and eventually cataractogenic.